Taste buds are found in a distributed array on the tongue surface, and are innervated by cranial nerves that convey taste information to the brain. For nearly a century, taste buds were thought to be induced by nerves late in embryonic development. Over the past decade, however, this view has shifted dramatically. A host of studies now indicate that taste bud development is initiated and proceeds via processes that are nerve- independent, occur long before birth, and are governed by cellular and molecular mechanisms intrinsic to the developing tongue. In mice, lingual taste buds reside in epithelial-mesenchymal specializations, termed taste papillae. The first indication of taste development is the appearance of taste placodes in the tongue surface at midgestation; it has been assumed that taste placodes morph into taste papillae, which then, around birth, produce taste buds from a subset of papilla epithelial cells. However, we have shown that taste placodes are actually taste bud precursor cells (TBPcs), which give rise to taste bud cells only, and not to taste papillae. These recent findings serve as the basis for our new model, one in which TBPc induction is the primary event in taste bud development, while taste papillae form in response to signals emitted from newly induced TBPcs. A number of signaling pathways are involved in the induction of TBPcs, most prominently Wnt/ss-catenin and Shh; these pathways also regulate later aspects of taste bud and papilla development. To date, we have focused on the functions of Wnt and Shh in lingual epithelium. However, because the developing tongue has both epithelial and mesenchymal compartments, and because taste papillae comprise a mesenchymal core surrounded by epithelium, interactions between lingual mesenchyme and epithelium also likely underlie development of the taste periphery. Using newly available conditional molecular genetic tools in mice, we propose to explore Shh and Wnt function in lingual mesenchyme and epithelium during precise and temporally separable aspects of taste organ development, testing the overarching hypothesis that: Development of taste buds is intrinsic to lingual epithelium, while taste papilla development is initiated by taste bud precursos and requires interactions between epithelium and mesenchyme. Aim 1. Define the roles of lingual epithelium and mesenchyme in the induction of taste bud precursors. Aim 2. Determine if morphogenesis of taste papillae requires receipt of signals from taste bud precursors. Aim 3. Test if autocrine signaling by taste bud precursors is required for taste cell differentiation. In elucidating these mechanisms, we will gain crucial insight into molecular genetic regulation of taste bud pattern and cell complement. In the long term, we will leverage these advances in our understanding to explore how taste bud variation influences taste preferences underlying healthy versus detrimental dietary choices. PUBLIC HEALTH RELEVANCE: Our sense of taste is mediated by taste buds on the tongue surface, and we use this sensory system to make key dietary decisions which impact our health, i.e., what to eat and what to avoid. In this application we will investigate how taste buds are established, with the long-term goal of understanding how taste bud development affects dietary choices of adults.